Double Clopidogrel Loading Dose Offers No Benefit in Primary PCI Patients with CKD

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Although patients with chronic kidney disease (CKD) typically have reduced responsiveness to clopidogrel, a Korean registry study suggests doubling the loading dose prior to primary percutaneous coronary intervention (PCI) does not improve short- or long-term outcomes. However, increasing the dose does not lead to increased bleeding or stroke, according to the findings published on line August 30, 2012, ahead of print in the American Journal of Cardiology.

Investigators led by Myung Ho Jeong, MD, PhD, of Chonnam National University (Gwangju, South Korea), examined data on clopidogrel loading dose in 1,457 patients with CKD from the Korea Acute Myocardial Infarction Registry (KAMIR). All patients underwent primary PCI for STEMI less than 24 hours after symptom onset. Patients received either the standard loading dose (300 mg; n = 596) or a higher loading dose (600 mg; n = 861) at the individual physician’s discretion.

No Short- or Long-term Advantage for Higher Loading Dose

Overall, in-hospital complication rates were similar for the 300-mg and 600-mg loading doses, including rates of stroke (1.7% vs. 0.7%; P = 0.13) and major bleeding (0.2% vs. 0.8%; P = 0.09). In addition, there were no differences between groups in rates of MACE (composite of cardiac death, noncardiac death, recurrent MI, TLR, and stent thrombosis), at 1 month (16.4% vs. 15.6%; P = 0.70) or 12 months (21.3% vs. 19.0%; P = 0.32).

On multivariate analysis, the 600-mg loading dose was not an independent predictor of 1-month or 12-month MACE. Factors that were independent predictors of MACE at both time points were ≤ LVEF 35%, cardiogenic shock and eGFR.

Analysis of 572 propensity-score matched patients from each  group again showed no differences in the frequency of in-hospital complications or 1- and 12-month clinical outcomes, except for a higher rate of noncardiac death with the 300 mg loading dose compared with the higher dose (4.2% vs. 1.7%; P = 0.024). Similarly, a 600-mg loading dose was not an independent predictor of 1- and 12-month MACE.

The authors offer several possible explanations for why the 600-mg loading dose was not more effective in this population. First, platelet response to clopidogrel varies by race, with previous studies reporting higher platelet reactivity after clopidogrel in Asians compared with Caucasians. However, this Korean cohort may not have achieved a level of platelet inhibition on the higher dose at which clinical benefits would appear.

“Second, CKD itself has a decreased antiplatelet drug effect, derived from an increase in the platelet turnover rate and poor bioavailability of the active clopidogrel metabolite,” they write. “Failure to overcome this decreased antiplatelet drug effect in patients with CKD could be another reason, and a loading dose of clopidogrel [greater than] 600 mg might be needed to gain desirable results,” the authors add.

Questions Remain

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said the findings are “provocative” since other data, particularly those from the PCI subgroup of CURRENT-OASIS 7, showed lower rates of cardiovascular death, MI, and stroke as well as a reduction in stent thrombosis with a higher loading dose of clopidogrel.

“Our own observations from the CHARISMA trial suggest there may be some sort of interaction with clopidogrel such that in patients with marked kidney dysfunction, it doesn’t work as well, but there are no hard data to support that,” he added.

Dr. Bhatt said an analysis from the PLATO trial of clopidogrel vs. ticagrelor in ACS patients suggested a greater benefit of ticagrelor vs. clopidogrel on top of aspirin as renal function worsened. “So, it’s conceivable that there is something here and that these patients may be analogous to those with diabetes who derive particular benefit from the more potent antiplatelet agents,” he commented. “The only word of caution is that patients with kidney dysfunction tend to bleed more, so if a physician is considering escalating the antithrombotic or antiplatelet therapy, they need to be very mindful of the patient’s bleeding risk, particularly if [the] patient has renal failure.”

However, in a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said the study was so underpowered that it is difficult to reach any conclusions about the impact of the higher clopidogrel dose. He added that the wide confidence intervals and sparse information on the exact nature of kidney dysfunction in the cohort also detract from its relevance.

Study Details

The median age was 71.6 years, and 57.2% were men. The median eGFR was 44.9 mL/min/1.73 m², and 13.8% had an eGFR less than 30 mL/min/1.73 m².

Baseline characteristics were generally well matched between the groups, except for higher systolic blood pressure and a higher prevalence of current smokers and previous regular aspirin use in the 300-mg loading dose group. In terms of procedural characteristics, use of low-molecular-weight heparin during hospitalization was more prevalent in the 300-mg group, but prescription rates of in-hospital and discharge antiplatelet agents, beta blockers, ACE inhibitors or angiotensin II receptor blockers, and statins were similar between groups.

Source:

Kim JY, Jeong MH, Moon JH, et al. Impact of clopidogrel loading dose in patients with chronic kidney disease undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am J Cardiol. 2012;Epub ahead of print.

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